Autres pays, autres coeurs? Dietary patterns, risk factors and ischaemic heart disease in Belfast and Toulouse.

The WHO MONICA project monitors trends and determinants in cardiovascular disease to relate classical risk factor changes to trends in incidence rates. The Belfast and Toulouse MONICA centres have also collaborated in dietary studies. Both centres have validated incidence and attack rates for ischaemic heart disease using coronary event registration. These data confirm that the disease in middle-aged men is between three and four times as common in Belfast as in Toulouse. Risk factor surveys show some differences between the centres, but the overall risks assessed by two multiple logistic function scoring systems were identical. A weighed dietary survey revealed no important difference in macronutrient intake, although carbohydrate and saturated fat intake in Belfast was significantly higher. Protein, dietary cholesterol and polyunsaturated fat, particularly linoleic acid intake, was significantly higher in Toulouse, as was consumption of wine, cheese, fruit and vegetables, but not potatoes. The Northern Irish diet is typically Northern European, but although the diet in Toulouse has some features of the Mediterranean diet, it is not appreciably different from that in Belfast in terms of total fat intake. Major differences are present for several food items, and in general these differences add support to the antioxidant hypothesis.

Human type II hyperlipoproteinemia enhances platelet-collagen adhesion in flowing nonanticoagulated blood.

We investigated the effects of high plasma lipid levels on platelet adhesion and platelet thrombus formation in nonanticoagulated human blood on collagen fibrils at an arterial wall shear rate of 2600 seconds-1. Nonanticoagulated blood was drawn directly at a flow rate of 10 mL/min for 3 minutes from an antecubital vein of patients with type IIa (n = 5) and type IIb (n = 4) hyperlipoproteinemia over purified human type III collagen fibrils that were positioned on a plastic coverslip in a parallel-plate perfusion chamber. Results were compared with those obtained in healthy individuals with normal lipid plasma levels (n = 9). Blood-collagen interactions were quantified by morphometry as platelet-collagen adhesion, thrombus volume, and fibrin deposition. Platelet-collagen adhesion in the two groups of patients was significantly higher than in healthy individuals (70.7 [61.2 to 82.0] and 70.3 [66.4 to 81.0] in types IIa and IIb patients, respectively, versus 51.2 [44.5 to 68.6] in control subjects; P < .05. All values are percent median [range]). In contrast, the thrombus volume was similar in the three groups (11.3 [8.0 to 13.0], 9.6 [6.4 to 15.3], and 10.2 [6.8 to 16.1] microns3/microns2 [range], respectively). Differences in fibrin deposition were not observed. Thus, it appears that platelet-collagen adhesion is augmented in patients with type IIa and IIb hyperlipoproteinemia, indicating that the process of thrombogenesis is hastened in these patients.

[A one-year prospective and intensive pharmacovigilance of antilipemic drugs in an hospital consultation for prevention of risk factors]. / Un an de pharmacovigilance prospective et intensive des médicaments hypolipidémiants dans une consultation hospitalière de prévention des facteurs de risque.

Cholesterol-lowering drugs include three major pharmacological classes: a) fibrates, b) statines, HMG-CoA reductase inhibitors and c) cholestyramine. The late eighties were characterized by the introduction of HMG-CoA reductase inhibitors in therapeutics. For 12 months (1st January-31 December 1991), a prospective intensive program of pharmacovigilance investigated the occurrence of side effects among the three pharmacological classes of cholesterol-lowering drugs in a specialized unit for prevention of atherosclerosis and dyslipidemia. Among 3,506 out patients who received cholesterol-lowering drugs, 36 side effects were reported (i.e. 1 side effect for 98 out-patients). Most of the side effects were observed with statines (61%). The most frequently observed side effects were gastralgia (19.5%) observed with the three classes of drugs and hepatitis with HMG-CoA reductase inhibitors (8.5%) or fibrates (3%) whereas myopathy (12%) only occurred with statines. The other side effects were cutaneous (14%: eczema, skin rashes) or neuropsychiatric (11%: insomnia...) ones. This study emphasizes the low frequency of severe side effects (myopathy: 1 per 1,000 prescriptions, hepatitis: 1 per 1,000 prescriptions) with cholesterol-lowering drugs in current practice.

[Systematic cardiovascular evaluation and hypercholesterolemia. Results in 200 asymptomatic patients]. / Bilan cardiovasculaire systématique et hypercholestérolémie. Résultats chez 200 patients asymptomatiques.

This study reports the results of routine evaluation to detect coronary and carotid atherosclerosis in 200 asymptomatic and hypercholesterolemic patients (48 +/- 10 years: 72.5% men). All patients underwent physical examination, blood lipid profile, an exercise test and cervical echo-doppler. If the exercise electrocardiogram was abnormal, a thallium isotope scan and/or coronary arteriography were performed. Hypercholesterolemia was severe (3.03 +/- 0.52 g/l). 77.5% of patients had pure hypercholesterolemia. Carotid atherosclerosis in the form of plaque (27.5%) or stenosis (3.5%) was found in 31% of patients. This carotid atheroma was commoner in older patients (51.9 +/- 9 years as against 47 +/- 10 years, p < 0.01). Twenty patients (10%) had electrical signs of ischemia provoked by exercise. Six of them had a normal thallium isotope scan and did not undergo coronary arteriography. Coronary arteriography was abnormal in 10 patients (5%): 7 had stenotic lesions and 3 showed evidence of spasm during the methylergometrine test. In total, the hypercholesterolemic patients investigated here were characterised by subclinical atherosclerosis which was frequent but certainly underestimated by non-invasive studies. The existence of an atherosclerotic lesion is an additional argument in favour of starting cholesterol-lowering treatment.

[Comparison of prognosis and treatment of myocardial infarction in Haute-Garonne between 1986 and 1989. MONICA project, Toulouse]. / Comparaison du pronostic et du traitement de l'infarctus du myocarde en Haute-Garonne entre 1986 et 1989. Projet MONICA-Toulouse.

The aim of this study, based on the data of the MONICA register in the Haute-Garonne, was to compare the prognosis and treatment of myocardial infarction between 1986 (253 cases) and 1989 (248 cases). The clinical features of these infarcts were comparable except for the previous history of ischaemic heart disease which was less common in 1989 (34.7% in 1986, 25.9% in 1989; p < 0.05). The 28th day mortality decreased from 8.4% in 1986 to 3.6% in 1989 without attaining statistical significance. The pre-hospital management was the same during the two periods of the study, with 67.6% of patients admitted to hospital before the 6th hour. Hospital care in 1986 and 1989 consisted of 5 days in the intensive care unit and lasted 14 days. Treatment changed considerably from 1986 to 1989. There was a higher incidence of platelet antiaggregant prescriptions (47.4% in 1986 and 80% in 1989; p < 0.001), of betablocker prescriptions (30.8% in 1986 and 47% in 1989; p < 0.05) and fibrinolytics (27.8% in 1986 and 52% in 1989; p < 0.01). Invasive procedures such as coronary angiography (83.5% in 1986 and 94% in 1989; p < 0.05), coronary angioplasty (20.3% in 1986 and 53.5% in 1989; p < 0.01) were undertaken in the majority of cases. The MONICA-Toulouse project shows a reduction in mortality and an increase in the use of therapeutic methods known to be effective in the reduction of mortality in myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease. The ECTIM Study.

The incidence of coronary heart disease (CHD) in middle-aged men is more than three times higher in Northern Ireland than in France. The ECTIM study, which is based on WHO MONICA centers in Belfast (Northern Ireland), Strasbourg (eastern France), Toulouse (southwestern France), and Lille (northern France), has been established to investigate this striking difference. Male patients aged 25-64 years with myocardial infarction (MI) and control subjects sampled from the general population were recruited in the four centers. Hypolipidemic drug treatment was much more frequent in France than in Belfast. "Hypercholesterolemia" defined by the presence of hypolipidemic drug treatment or a low density liproprotein cholesterol level greater than 200 mg/dl was more frequent in cases than in controls in both countries but was similar in both control groups. An in-depth study of lipid variables, including measurements of cholesterol fractions, triglycerides, apolipoproteins (apo), and lipoprotein particles (Lp), was performed in nonhypercholesterolemic subjects. In Northern Ireland and France, patients in comparison with controls had lower levels of high density lipoprotein cholesterol, apo A-I, apo A-II, Lp A-I, and Lp A-II:A-I and higher levels of Lp E:B and Lp(a):B. The levels of triglycerides, very low density lipoprotein cholesterol, apo B, and Lp C-III:B were higher in cases than in controls only in Belfast. In control subjects, the mean levels of cholesterol fractions and apolipoproteins were similar in Northern Ireland and France; however, the level of Lp A-I was lower and the levels of Lp E:B and Lp(a):B were higher in Northern Ireland than in France.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.

Screening for new mutations in the LDL receptor gene in seven French familial hypercholesterolemia families by the single strand conformation polymorphism method.

To investigate the molecular basis of familial hypercholesterolemia (FH) in France, we applied the single strand conformation polymorphism (SSCP) method to the promoter region and the 18 exons of the low density lipoprotein receptor (LDLR) gene. Seven probands, 4 heterozygotes, 2 compound heterozygotes, and 1 homozygote, belonging to FH families were tested. In all cases, previous genetic analysis and/or LDL receptor fibroblast assay had shown that the disease was due to defects in the LDLR gene. Out of the nine mutations expected, one nonsense mutation in exon 2 and six missense mutations were identified in exons 3, 6, 8, 11, and 15. Two of the latter were found in exon 6. In each family, cosegregation of the base substitution and the disease was observed. Ninety-five control subjects were screened for the presence of the six missense mutations. None was detected, implying that the mutations identified are deleterious. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used to rapidly screen mutation containing exons in large genes. Furthermore, all these mutations are newly described and demonstrate heterogeneity of LDLR gene mutations responsible for FH in the French population, as in other reported Caucasian populations.

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

[Regression of a coronary atheroma. Proof and doubts]. / Régression de l'athérome coronarien. Preuves et incertitudes.

The regression of coronary atheroma appears to have been convincingly demonstrated by epidemiology or experimental models. Studies involving prevention based upon influencing the lipid factor have clearly shown a decrease in coronary events when drugs cause a lowering of blood lipids. Atheromatous lesions induced in the animal regress if exposure to the factors which have favourised these lesions is eliminated. Studies in man have confirmed the regression of atherosclerotic lesions in several vascular areas. Atheromatous coronary stenoses appear to regress or stabilise, essentially under the influence of hypolipidemic agents but also that of calcium inhibitors, platelet anti-agregants and, probably, anti-oxidising drugs. The clinical value of these therapeutic actions remains to be evaluated and the fate of fibrous lesions is not known. In contrast, relatively early lesions may already derive benefit from this new concept. Methods for assessment of regression in man nevertheless remain imperfect and require a very strict study protocol and methodology.

[The efficacy and tolerance of simvastatin and fenofibrate in primary hypercholesterolemia]. / Efficacité et tolérance de la simvastatine et du fénofibrate dans l'hypercholestérolémie primaire.

The effects of simvastatin and fenofibrate on blood lipids and the side-effects of these two drugs were compared in a double-blind trial involving 184 adults with primary hypercholesterolemia (total cholesterol levels: 3.87 +/- 1.02 g/l in the simvastatin group, 3.78 +/- 0.79 g/l in the fenofibrate group; N.S.). During a 10-week period, the patients received either fenofibrate 200 mg twice daily or simvastatin 20 mg once daily with doubling of the dosage at week 6 if the LDL-cholesterol level remained above 1.40 g/l. Simvastatin significantly (P less than 0.01) reduced total cholesterol by -29.9 percent, LDL-cholesterol by -35.4 percent, apoprotein B by -27.3 percent and triglycerides by -16.7 percent. Fenofibrate significantly (P less than 0.01) reduced total cholesterol by -19.2 percent, LDL-cholesterol by -22.3 percent apoprotein B by 13.9 percent and triglycerides by 28.9 percent. Reduction of the first 3 parameters was significantly (P less than 0.01) greater with simvastatin and reduction of triglycerides significantly greater with fenofibrate. Apoprotein A1 levels were increased by fenofibrate (+ 7.4 percent) but not by simvastatin. Side-effects occurred with a frequency of 6 percent under simvastatin and 9 percent under fenofibrate.

[Evaluation of mortality caused by ischemic heart disease in Haute-Garonne]. / Evaluation des décès par cardiopathie ischémique en Haute-Garonne.

The mortality due to ischemic heart disease may be assessed in the department of the Haute Garonne from a Register of cardiovascular disease. In this study the medical causes of death codified using the normal criteria of international classification of disease were compared with the causes of death classified according to the criteria of the Register determined in the same subjects after a complementary enquiry. Between July 1st 1984 and December 31st 1986, 800 consecutive cases of patients dying of cardiovascular disease aged 25 to 64 years at death were examined. A complementary enquiry into the cases of these patients was undertaken involving the treating physician and hospital establishments in order to determine the mode of death and to obtain clinical, ECG, biological and when possible autopsy results for each case. The sensitivity and specificity of the causes of death coded 410-414 according to the criteria of international classification of disease was 74 and 71 p. 100 respectively. The positive predictive value was 75 p. 100 and the value of the kappa index was 0.44. Therefore, the concordance between the causes of death codified by the usual classification and those codified after a thorough complementary enquiry was not very close. On the other hand, taken as a whole, the number of deaths due to ischemic heart disease by the international coding system (428 cases) was 2.1 p. 100 less than that observed after the complementary enquiry (437 cases). These results should, however, be interpreted with caution because of the high proportion (34%) of cases in which the cause of death could not be determined with precision even after the complementary enquiry.(ABSTRACT TRUNCATED AT 250 WORDS)

[Primary results of the MONICA project]. / Les premiers enseignements du projet MONICA.

The MONICA project is an international study coordinated by the WHO, designed to explain the important variations of coronary mortality observed in the industrialised countries over the last 20 years. Thirty-nine centres in 27 countries are participating in the project which, over a 10 year period will, in geographically determined zones; a) record the numbers of acute myocardial infarcts and coronary deaths, b) analyse the treatment of acute cardiac events, and c) evaluate the cardiovascular risk factors and preventive measures in the general population. The MONICA-France project comprises three registers (Bas-Rhin, Haute-Garonne and the urban community of Lille), and a coordinating centre. The preliminary results confirm the wide geographic variability of coronary mortality with a prevalence slightly higher in Alsace and the North than in the South-West of France. The approximative frequency of coronary events in France is estimated at 112,000 infarcts and over 175,000 acute coronary episodes and deaths. Information is provided about the severity of the principal coronary risk factors and the conditions of their treatment in the register zones. A study of the accessibility of emergency treatment of acute infarction in the Bas-Rhin area, has demonstrated the key role of the general practitioner as the first contact but confirmed the long delay to hospital admission which nullified the potential benefits of thrombolysis in a high proportion of cases. However, the significant decrease in hospital mortality of acute infarction observed over a 3 year period in the three register zones, is probably related to the number of patients thrombolysed in that time.

Effect of pravastatin, an HMG CoA reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by their apolipoprotein composition.

This study compares the effects of cholestyramine (16 g/d) and pravastatin (40 mg/d) on lipoprotein particles defined by their apolipoprotein composition (Lp A-I, Lp A-II:A-I, Lp E:B, and Lp C-III:B). Analysis was performed after 4, 8, and 12 weeks of therapy. Low-density lipoprotein (LDL) cholesterol decreased by 25.1% to 35.0% with cholestyramine and 26.2% to 30.7% with pravastatin, while triglycerides decreased slightly with pravastatin therapy and increased slightly during cholestyramine administration. The fall in cholesterol was mainly due to a decrease in very-low-density lipoprotein (VLDL) and LDL cholesterol; high-density lipoprotein (HDL) cholesterol increased. Apolipoprotein B was reduced dramatically (by 21.7% to 30.5% with cholestyramine and 27.7% to 37.4% with pravastatin). No significant effect on apolipoproteins C-III and E was observed with cholestyramine, while pravastatin reduced these parameters slightly. Apolipoprotein A-I increased during therapy with both drugs, while apolipoprotein A-II was slightly decreased. Although the drugs had nearly the same effects on plasma lipids, their influence on lipoprotein particles defined by their apolipoprotein composition was substantially different. Lp A-II:A-I was increased by both drugs (+8.1% to +41.2% for cholestyramine and +7.2% to +32.6% for pravastatin). Lp A-I was also increased with both drugs, but cholestyramine had a more constant and pronounced effect than pravastatin (+15.1% to +21.7% for cholestyramine and +1.7% to +13.0% for pravastatin). Lp E:B and Lp C-III:B were consistently decreased by pravastatin (-10.2% to -36.5% for LP E:B and -7.2% to -20.9% for Lp C-III:B), while cholestyramine had variable effects on these particles.(ABSTRACT TRUNCATED AT 250 WORDS)

A LDL receptor gene homozygous mutation: PCR amplification, direct genomic sequencing, associated haplotype, rapid screening for frequency.

Many mutations in the LDL receptor (LDLR) gene have now been identified mostly as gross gene rearrangements, however they only represent a weak percentage of all deleterious gene mutations causing Familial Hypercholesterolemia (FH). This discrepancy may be related to the difficulties in characterizing point or small defective mutations. In a three-generation family with Familial Hypercholesterolemia, one specific haplotype constructed with 12 intragenic restriction fragment length polymorphisms (RFLP) cosegregated with the disease, while in the consanguineous propositus there was homozygosity for this haplotype. By polymerase chain reaction (PCR) amplification followed by direct sequencing there was unequivocal evidence for a double dose of a unique mutation, (namely a duplication of 4 bases in exon 17), while there was a single dose in heterozygote relatives. We consequently screened a population selected under clinical and geographical criteria for this mutation by PCR and allele specific oligonucleotides (ASO) hybridization. None of the 158 type IIa individuals tested carried the same mutation. Herein, is a rapid combined genetic and molecular approach to characterize and evaluate the frequency of LDL Receptor gene mutations causing Familial Hypercholesterolemia, towards targeted prevention and therapy.

Between-register and within-register variability in event-finding and rates in the MONICA-France Project.

The 1985 and 1986 coronary event data from the three French MONICA Registers in Haute-Garonne (Toulouse), Bas-Rhin (Strasbourg) and the Urban Community of Lille (UCL) are used to compare the sources of information, the distribution of events in different diagnostic categories, and their possible effects on event rates. All three registers follow the MONICA protocol, and use the "cold pursuit" method, with data abstracted retrospectively from medical files or from the doctors establishing the causes of death. The health system and medical background are similar in the three centers. The distribution of the sources of information (in-hospital and out-of-hospital) and the distribution of events by diagnostic categories are different among centres. The possible effects of these differences on rates of definite myocardial infarction or possible coronary death are estimated between registers and within registers during a 2-year period. Cross-sectional comparisons are questionable, and possible false trends in event rates require special attention.

Comparison of dietary patterns between population samples in the three French MONICA nutritional surveys.

A nutritional survey was carried out from 1985 to 1987 in three French areas covered by the ischaemic heart disease registers: Bas-Rhin (BR), Haute-Garonne (HG) and the Urban Community of Lille (UCL). 1,128 men aged 45-64 were included in a survey, using the 3-day record method. The results, after adjustment for age, socio-economic status, residence and prescribed diet, showed differences, sometimes significant, between the three samples. Fat represented 37% of the total energy intake in BR, 36% in UCL, and 34% in HG. The P:S ratio ranged from 0.50 in HG, to 0.47 in BR, and 0.40 in UCL. These differences were due to a higher intake of vegetable fat and a lower intake of animal fat in HG. In spite of a very important alcohol intake, with no big differences between the centres (33 to 36 g/day), we noticed that HG drank mainly wine, whereas BR and UCL drank wine and beer in about the same proportions.

[Cholesterol: from where does it come, how does it circulate, where does it go?]. / Le cholestérol: d'où vient-il, comment circule-t-il, où va-t-il?

Cholesterol is an essential component of cell membranes. It is present in food and partially absorbed by the gut, but it is also synthesized by every cell in the body. However, only enterocytes and hepatocytes play a quantitatively important role in the synthesis of cholesterol that is present in plasma. Cholesterol is transported by complex particles, called lipoproteins, which have specific proteins on their surface. These proteins, called apolipoproteins, have an essential function in the metabolism of lipoproteins. Low-density lipoproteins (LD) transport the majority of cholesterol in normal human plasma and distribute it to peripheral tissues. They bind to a specific cell receptor (LDL-receptor), and after endocytosis the intracellular cholesterol will be used to build cell membranes and to synthesize other molecules (biliary acids, hormones). The cholesterol present in peripheral tissues is taken up by high-density lipoproteins (HDL) and transferred to LDL. The latter particles are then degraded by the liver, and cholesterol is excreted in the bile.